Intratumoral microbiota of pancreatic ductal adenocarcinoma impact patient prognosis by influencing tumor microenvironment.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a highly metastatic potential and a heterogeneous tumor microenvironment. It exhibits limited sensitivity to conventional therapies, necessitating a deeper understanding of its pathogenesis. The role of the intratumoral microbiome in regulating cancer development in PDAC has been the subject of debate. Previous investigations into intra-tumor microbiomes have yielded uncertain results due to sample size limitations and insufficient decontamination procedures. Further research is imperative to elucidate the intricate relationship between intra-tumor microbiomes, the immune landscape of PDAC, and overall prognosis. RESULTS: Our findings revealed that the intratumor microbiota in PDAC tissue exhibited lower diversity and distinct communities compared to non-tumor tissues. The top microorganisms distinguishing between patients with long or short survival were used to construct the risk signature. We found that Stenotrophomonas is implicated in short survival of PDAC patients, while Neorickettia and Mediterraneibacter are correlated with long survival. This microbiome-based PDAC subtyping, grounded in prognosis-related signatures, exhibited significant correlations with distinct clinical prognoses and immune microenvironments. Microorganisms associated with negative prognoses were linked to pro-tumor immune activation, while those associated with positive prognoses were linked to anti-tumor immune response activation and a more favorable prognosis. CONCLUSIONS: Our PDAC subtyping approach, based on a microbiome-derived prognostic risk signature, unveiled compelling associations between the PDAC microbiota and disparities in both clinical prognosis and the tumor microenvironment. These findings suggest that microbiota may serve as a promising biomarker for predicting the prognosis of PDAC.

Adolescent F-53B exposure induces ovarian toxicity in rats: Autophagy-apoptosis interplay.

As a substitute for perfluorooctane sulfonates, F-53B has permeated into the environment and can reach the human body through the food chain. Adolescent individuals are in a critical stage of development and may be more sensitive to the impacts of F-53B. In the present study, we modeled the exposure of adolescent female rats by allowing them free access to F-53B at concentrations of 0 mg/L, 0.125 mg/L, and 6.25 mg/L in drinking water, aiming to simulate the exposure in the adolescent population. Using the ovary as the focal point, we investigated the impact of developmental exposure to F-53B on female reproduction. The results indicated that F-53B induced reproductive toxicity in adolescent female rats, including ovarian lesions, follicular dysplasia and hormonal disorders. In-depth investigations revealed that F-53B induced ovarian oxidative stress, triggering autophagy within the ovaries, and the autophagy exhibited the interplay with apoptosis in turn, collectively leading to significant ovarian toxicity. Our findings provided deeper insights into the roles of the autophagy-apoptosis interplay in ovarian toxicity, and offered a new perspective on the developmental toxicity inflicted by adolescent F-53B exposure.

Associations of urinary heavy metals with age at menarche, age at menopause, and reproductive lifespan: A cross-sectional study in U.S. women.

Female reproductive timing and lifespan, with a close relation to long-term health outcomes, have been altered in U.S. women over the past decades. However, epidemiologic evidence of the potential causes was lacking. On the basis of 1981 naturally postmenopausal women from the National Health and Nutrition Examination Survey 1999-2020, this study aimed to investigate the associations of urinary heavy metals with age at menarche, age at menopause, and reproductive lifespan. Multivariate generalized linear regression and addictive models were used for single metal exposure analysis, and weighted quantile sum (WQS) and Bayesian kernel machine regression (BKMR) models were employed for mixed exposures. In the fully adjusted model, higher urinary antimony concentration was associated with earlier age at menarche of 0.137 years, while higher concentrations of cadmium, cesium, lead, antimony, and thallium were associated with delayed age at menopause of 0.396-0.687 years. Additionally, urinary barium, cesium, lead, antimony, and thallium levels were associated with longer reproductive lifespan ranging between 0.277 and 0.713 years. Both WQS and BKMR models showed significantly positive associations of metal mixtures with age at menopause (ß: 0.667, 95 % CI: 0.120-1.213) and reproductive lifespan (ß: 0.686, 95 % CI: 0.092-1.280), with cadmium and lead identified as principal contributors. In conclusion, heavy metal exposures were associated with reproductive timing and lifespan of U.S. women, highlighting the need for further prevention and intervention strategies.

Gender differences in attitudes towards psychological help-seeking among chinese medical students: a comparative analysis.

BACKGROUND: Medical students are known to be at a greater risk of psychological disorders compared to the general population. However, their rate of help-seeking behavior is low. The purpose of this study was to explore the influencing factors of attitudes towards psychological help-seeking among Chinese medical students and to examine its gender differences. METHODS: A total of 3,453 medical students from three medical colleges in Hainan Province, China, completed anonymous questionnaires that included socio-demographic attributes, the Family APGAR Index, the General Health Questionnaire (GHQ-20), and the Attitudes Towards Seeking Professional Psychological Help Short Form (ATSPPH-SF). Associations between predictor variables and attitudes towards help-seeking were explored using multivariate linear regression, and regression models with interaction terms were employed to test gender difference. RESULTS: The mean score on ATSPPH-SF Scale was 15.04 ± 3.45, with males scoring significantly lower than females (14.34 vs. 15.64, P < 0.0001). For both male and female groups, psych knowledge, mental health status, family function and help-seeking utility perception significantly influenced attitudes toward psychological help-seeking. Furthermore, having more than once psycho-help experiences was positively correlated with women's attitudes. Significant interactions were found between gender and mental health status. CONCLUSION: Attitude towards seeking psychological help was relatively negative among Chinese medical students. The implementation of interventions should take into account the at-risk population, especially the males and individuals with poor mental health.

Maternal F-53B exposure during pregnancy and lactation affects bone growth and development in male offspring.

6:2 Chlorinated polyfluoroalkyl ether sulfonate (F-53B) is a new type of perfluorinated and polyfluoroalkyl substance (PFAS) that is used extensively in industry and manufacturing. F-53B causes damage to multiple mammalian organs. However, the impacts of F-53B on bone are unknown. Maternal exposure to F-53B is of particular concern because of the vulnerability of the developing fetus and newborn to contaminants from the mother. The goal of this study was to examine the impacts of maternal F-53B exposure on bone growth and development in offspring and to explore its underlying mechanisms. Herein, C57BL/6 J mice were given free access to deionized water containing 0, 0.57, or 5.7 mg/L F-53B during pregnancy and lactation. F-53B exposure resulted in impaired liver function, decreased IGF-1 secretion, dysregulation of bone metabolism and disruption of the dynamic balance between osteoblasts and osteoclasts in male offspring. F-53B inhibits longitudinal bone growth and development and causes osteoporosis in male offspring. F-53B may affect the growth and development of offspring bone via the IGF-1/OPG/RANKL/CTSK signaling pathway. This study provides new insights for the study of short stature and bone injury caused by F-53B.

Biochemical and structural insights into a 5' to 3' RNA ligase reveal a potential role in tRNA ligation.

ATP-grasp superfamily enzymes contain a hand-like ATP-binding fold and catalyze a variety of reactions using a similar catalytic mechanism. More than 30 protein families are categorized in this superfamily, and they are involved in a plethora of cellular processes and human diseases. Here we identify C12orf29 as an atypical ATP-grasp enzyme that ligates RNA. Human C12orf29 and its homologs auto-adenylate on an active site Lys residue as part of a reaction intermediate that specifically ligates RNA halves containing a 5'-phosphate and a 3'-hydroxyl. C12orf29 binds tRNA in cells and can ligate tRNA within the anticodon loop in vitro. Genetic depletion of c12orf29 in female mice alters global tRNA levels in brain. Furthermore, crystal structures of a C12orf29 homolog from Yasminevirus bound to nucleotides reveal a minimal and atypical RNA ligase fold with a unique active site architecture that participates in catalysis. Collectively, our results identify C12orf29 as an RNA ligase and suggest its involvement in tRNA biology.

Senataxin deficiency disrupts proteostasis through nucleolar ncRNA-driven protein aggregation.

Senataxin is an evolutionarily conserved RNA-DNA helicase involved in DNA repair and transcription termination that is associated with human neurodegenerative disorders. Here, we investigated whether Senataxin loss affects protein homeostasis based on previous work showing R-loop-driven accumulation of DNA damage and protein aggregates in human cells. We find that Senataxin loss results in the accumulation of insoluble proteins, including many factors known to be prone to aggregation in neurodegenerative disorders. These aggregates are located primarily in the nucleolus and are promoted by upregulation of non-coding RNAs expressed from the intergenic spacer region of ribosomal DNA. We also map sites of R-loop accumulation in human cells lacking Senataxin and find higher RNA-DNA hybrids within the ribosomal DNA, peri-centromeric regions, and other intergenic sites but not at annotated protein-coding genes. These findings indicate that Senataxin loss affects the solubility of the proteome through the regulation of transcription-dependent lesions in the nucleus and the nucleolus.

Multimodal analysis of cfDNA methylomes for early detecting esophageal squamous cell carcinoma and precancerous lesions.

Detecting early-stage esophageal squamous cell carcinoma (ESCC) and precancerous lesions is critical for improving survival. Here, we conduct whole-genome bisulfite sequencing (WGBS) on 460 cfDNA samples from patients with non-metastatic ESCC or precancerous lesions and matched healthy controls. We develop an expanded multimodal analysis (EMMA) framework to simultaneously identify cfDNA methylation, copy number variants (CNVs), and fragmentation markers in cfDNA WGBS data. cfDNA methylation markers are the earliest and most sensitive, detectable in 70% of ESCCs and 50% of precancerous lesions, and associated with molecular subtypes and tumor microenvironments. CNVs and fragmentation features show high specificity but are linked to late-stage disease. EMMA significantly improves detection rates, increasing AUCs from 0.90 to 0.99, and detects 87% of ESCCs and 62% of precancerous lesions with >95% specificity in validation cohorts. Our findings demonstrate the potential of multimodal analysis of cfDNA methylome for early detection and monitoring of molecular characteristics in ESCC.

Fluorescent biosensor based on magnetic separation platform and spore-like breakable organosilica nanocapsules controlled-release carbon dots for the detection of Escherichia coli O157:H7.

Ultrasensitive and rapid detection of low concentration of Escherichia coli O157: H7 (E. coli O157:H7) in food is essential for food safety and public health. In this study, A novel fluorescence signal amplification biosensor based on magnetic separation platform and red fluorescent carbon dots (R-CDs)-encapsulated breakable organosilica nanocapsules (BONs) for ultrasensitive detection of E. coli O157:H7 was established. Wulff-type boronic acid functionalized magnetic nanoparticles (MNPs@B-N/APBA) with broad-spectrum bacterial recognition ability were synthesized for the first time to recognize and capture E. coli O157: H7 in food samples. R-CDs@BONs labeled with anti-E. coli O157:H7 monoclonal antibody (mAb@R-CDs@BONs-NH2) were used as the second recognition element to ensure the specificity for E. coli O157:H7 and form MNPs@B-N/APBA∼ E. coli O157:H7∼mAb@R-CDs@BONs-NH2 sandwich complexes, followed by releasing R-CDs to generate amplified fluorescence response signals for quantitative detection of E. coli O157:H7. The proposed method had a limit of detection with 25 CFU/mL in pure culture and contaminated lettuce samples, which the whole detection process took about 120 min. This fluorescence signal amplification biosensor has the potential to detect other pathogens in food by altering specific antibodies.

Polystyrene microplastics disturb maternal glucose homeostasis and induce adverse pregnancy outcomes.

Pregnant women are a special group that is sensitive to adverse external stimuli, causing metabolic abnormalities and adverse pregnancy outcomes. Microplastics (MPs), an environmental pollutant widely used in various fields, can induce a variety of toxic responses in mammals. Recent studies verified an association between MPs and metabolic disorders. Our research built a gestational mouse model in which polystyrene microplastics (PS-MPs) of 1 µm size were consumed at concentrations of 0.1, 1, and 10 mg/L during pregnancy. Results indicated that PS-MPs induced placental malfunction and fetal growth retardation. Significant glucose disorders, decreased liver function, hepatic inflammation, and oxidative stress were also observed after PS-MPs exposure. The hepatic SIRT1/IRS1/PI3K pathway was inhibited in the 10 mg/L PS-MPs exposure group. Our study found that PS-MPs activated inflammatory response and oxidative stress by increasing hepatic lipopolysaccharide (LPS) that inhibited the hepatic SIRT1/IRS1/PI3K pathway, ultimately leading to insulin resistance, glucose metabolism disorders, and adverse pregnancy outcomes. This study provides a basis for preventing environment-related gestational diabetes and concomitant adverse pregnancy outcomes.

Metal-polyphenol coordination nanosheets with synergistic peroxidase-like and photothermal properties for efficient antibacterial treatment.

Bacterial infections pose a serious threat to human health and socioeconomics worldwide. In the post-antibiotic era, the development of novel antimicrobial agents remains a challenge. Polyphenols are natural compounds with a variety of biological activities such as intrinsic antimicrobial activity and antioxidant properties. Metal-polyphenol obtained by chelation of polyphenol ligands with metal ions not only possesses efficient antimicrobial activity but also excellent biocompatibility, which has great potential for application in biomedical and food packaging fields. Herein, we developed metal-polyphenol coordination nanosheets named copper oxidized tannic acid quinone (CuTAQ) possessing efficient antibacterial and anti-biofilm effects, which was synthesized by a facile one-pot method. The synthesis was achieved by chelation of partially oxidized tannic acid (TA) with Cu2+ under mild conditions, which supports low-cost and large-scale production. It was demonstrated that CuTAQ exhibited high antibacterial activity via disrupting the integrity of bacterial cell membranes, inducing oxidative stress, and interfering with metabolism. In addition, CuTAQ exhibits excellent peroxidase catalytic activity and photothermal conversion properties, which play a significant role in enhancing its bactericidal and biofilm scavenging abilities. This study provides insights for rational design of innovative metal-polyphenol nanomaterials with efficient antimicrobial properties.

F-53B mediated ROS affects uterine development in rats during puberty by inducing apoptosis.

Perfluoroalkyl and polyfluoroalkyl substances (PFASs), as pollutants, can cause palpable environmental and health impacts around the world, as endocrine disruptors, can disrupt endocrine homeostasis and increase the risk of diseases. Chlorinated polyfluoroalkyl ether sulfonate (F-53B), as a substitute for PFAS, was determined to have potential toxicity. Puberty is the stage when sexual organs develop and hormones change dramatically, and abnormal uterine development can increase the risk of uterine lesions and lead to infertility. This study was designed to explore the impact of F-53B on uterine development during puberty. Four-week-old female SD rats were exposed to 0.125 and 6.25 mg/L F-53B during puberty. The results showed that F-53B interfered with growth and sex hormone levels and bound to oestrogen-related receptors, which affected their function, contributed to the accumulation of reactive oxygen species, promoted cell apoptosis and inhibited cell proliferation, ultimately causing uterine dysplasia.

Self-aspiration sampling design for rapid analyses of volatile organic compounds based on atmospheric pressure chemical ionization/photoionization combined ionization source mass spectrometry.

Development of combined mass spectrometry ionization sources has enabled expansion of the application and scope of mass spectrometry. A novel hybrid ionization system combining vacuum ultraviolet (VUV) and atmospheric pressure chemical ionization (APCI) was constructed. Gaseous samples were self-aspirated into an ionization zone through a capillary by negative pressure, generated by high-speed airflow based on the Venturi effect. Compared with APCI mode alone, the signal-to-noise ratio (S/N) in APCI/VUV mode was increased by about 276-times. To increase the ionization efficiency further, correlated experimental conditions were optimized. Four types of volatile organic compounds (VOCs) were tested to evaluate the performance of the APCI/VUV ion source. Excellent linearity and limit of detection were achieved for compounds in mixed solutions. Quantitative analyses of four VOCs (toluene, cyclohexanone, styrene and ethylbenzene) using APCI/VUV-MS were done, and the relative standard deviations (RSDs) were 1.57%, 6.30%, 4.49% and 8.21%, respectively, indicating that the APCI/VUV ionization source had excellent reproducibility. Our results demonstrated that the developed method was promising for analyzing VOCs as well as being rapid, simple, and easy to operate.

An antimicrobial film of silver/nanocellulose crystal/oxalic acid/polyvinyl alcohol with real-time bactericidal and prevention of biofilm formation properties.

Silver nanoparticles (AgNPs) is an excellent antibacterial agent, which is widely used in medical, food, environmental and other fields, but AgNPs are easy to accumulate in aqueous solution, so their application in various fields is limited. Therefore, it is particularly important to propose a new application method or to prepare a new composite material. In this study, OA/PVA was obtained by cross-linking oxalic acid (OA) with polyvinyl alcohol (PVA). Then Ag/NCC was obtained by in situ reduction of AgNPs on nanocellulose crystals (NCC). Finally, Ag/NCC/OA/PVA composite antimicrobial films with good waterproofing effect were prepared by mixing Ag/NCC with OA/PVA. Subsequently, the films were characterized using SEM, UV-vis, FTIR and XRD, as well as physicochemical properties such as mechanical strength and hydrophilic properties were determined. The results indicated that the Ag/NCC/OA/PVA films possess good light transmittance, mechanical properties, water resistance, antibacterial activity, and biodegradability. The results of the mechanism study showed that Ag/NCC/OA/PVA films can destroy cell integrity, inhibit succinate dehydrogenase (SDH) activity, thereby reducing intracellular ATP levels. And induce a large number of reactive oxygen species (ROS) production, eventually leading to the death of C. sakazakii. In summary, Ag/NCC/OA/PVA film has good physical and chemical properties, antibacterial activity and biocompatibility, and has promising applications in food and medical antibacterial fields.

Polystyrene microplastic-induced endoplasmic reticulum stress contributes to growth plate endochondral ossification disorder in young rat.

BACKGROUND: Previous studies on the effects of microplastics (MPs) on bone in early development are limited. This study aimed to investigate the adverse effects of MPs on bone in young rats and the potential mechanism. METHODS: Three-week-old female rats were orally administered MPs for 28 days, and endoplasmic reticulum (ER) stress inhibitor salubrinal (SAL) and ER stress agonist tunicamycin (TM) were added to evaluate the effect of ER stress on toxicity of MPs. The indicators of growth and plasma markers of bone turnover were evaluated. Tibias were analyzed using micro-computed tomography (micro-CT). Histomorphological staining of growth plates was performed, and related gene expression of growth plate chondrocytes was tested. RESULTS: After exposure of MPs, the rats had decreased growth, shortened tibial length, and altered blood calcium and phosphorus metabolism. Trabecular bone was sparse according to micro-CT inspection. In the growth plate, the thickness of proliferative zone substantial reduced while the thickness of hypertrophic zone increased significantly, and the chondrocytes were scarce and irregularly arranged according to tibial histological staining. The transcription of the ER stress-related genes BIP, PERK, ATF4, and CHOP dramatically increased, and the transcription factors involved in chondrocyte proliferation, differentiation, apoptosis, and matrix secretion were aberrant according to RT-qPCR and western blotting. Moreover, the addition of TM showed higher percentage of chondrocyte death. Administration of SAL alleviated all of the MPs-induced symptoms. CONCLUSION: These results indicated that MPs could induce growth retardation and longitudinal bone damage in early development. The toxicity of MPs may attribute to induced ER stress and impaired essential processes of the endochondral ossification after MPs exposure.

Bacterial detection based on Förster resonance energy transfer.

The huge economic loss and threat to human health caused by bacterial infection have attracted the public's concern, and there is an urgent need to relieve and improve the tough problem. Therefore, it is significant to establish a facile, rapid, and sensitive method for bacterial detection considering the shortcomings of existing methods. Förster resonance energy transfer (FRET)-based sensors have exhibited immense potential and applicability for bacterial detection given their high signal-to-noise ratio and high sensitivity. This review focuses on the development of FRET-based fluorescence assays for bacterial detection. We summarize the principle of FRET-based assays, discuss the commonly used recognition molecules and further introduce three frequent construction strategies. Based on the strategies and materials, relevant applications are presented. Moreover, some restrictions of FRET fluorescence sensors and development prospects are discussed. Suitable donor-acceptor pairs and stable recognition molecules are the essential conditions for sensors to play their roles, and there is still some room for development. Besides, applying FRET fluorescence sensors to point-of-care detection is still difficult. Future developments could focus on near-infrared fluorescent dyes and simultaneous detection of multiple analytes.

A novel approach to wound healing: Green synthetic nano-zinc oxide embedded with sodium alginate and polyvinyl alcohol hydrogels for dressings.

Wound healing constitutes a formidable challenge within the healthcare system, attributable to infection risks and protracted recovery periods. The pressing need for innovative wound healing methods has spurred the urgency to develop novel approaches. This study sought to advance wound healing by introducing a novel approach employing a composite sponge dressing. The composite sponge dressing, derived from LFL-ZnO (synthesized through the green methodology utilizing Lactobacillus plantarum ZDY2013 fermentation liquid), polyvinyl alcohol (PVA), and sodium alginate (SA) via a freeze-thaw cycle and freeze-drying molding process, demonstrated notable properties. The findings elucidate the commendable swelling, moisturizing, and mechanical attributes of the SA/LFL-ZnO/PVA composite sponge dressing, characterized by a porous structure. Remarkably, the dressing incorporating LFL-ZnO exhibited substantial inhibition against both methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus aureus (S. aureus). Hemolysis and cytotoxicity tests corroborated the excellent biocompatibility of the sponge dressing. In vivo evaluation of the therapeutic efficacy of the 1 mg/mL LFL-ZnO composite dressing on scald wounds and S. aureus-infected wounds revealed its capacity to accelerate wound healing and exert pronounced antibacterial effects. Consequently, the composite sponge dressings synthesized in this study hold significant potential for application in wound treatment.

Protective effect of Luffa cylindrica fermentation liquid on cyclophosphamide-induced premature ovarian failure in female mice by attenuating oxidative stress, inflammation and apoptosis.

Premature ovarian failure (POF) is a leading cause of women's infertility without effective treatment. The purpose of this study was to investigate the protective effects of Luffa cylindrica fermentation liquid (LF) on cyclophosphamide (CTX) -induced POF in mice and to preliminarily investigate the underlying mechanisms. Thirty-two Balb/c mice were divided into four groups randomly. One group served as the control, while the other three received CTX injections to establish POF models. A 14-day gavage of either 5 or 10 µL/g LF was administered to two LF pretreatment groups. To analyze the effects of LF, the ovarian index, follicle number, the levels of serum sex hormones, superoxide dismutase (SOD), glutathione (GSH), malondialdehyde (MDA), inflammatory factors, and apoptosis of the ovarian cells were measured. The effects of LF pretreatment on the expression of TLR4/NF-κB and apoptosis pathways were also evaluated. We found that LF pretreatment increased the ovarian index and the number of primordial and antral follicles while decreasing those of atretic follicles. LF pretreatment also increased the serum levels of estradiol (E2) and anti-Müllerian hormone (AMH), while decreasing those of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Furthermore, LF pretreatment increased the levels of SOD and GSH in the ovaries, while decreasing those of MDA, tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß). LF administration reduced the amount of TUNEL+ ovarian cells and the levels of TLR4 and NF-κB P65 protein expression. In conclusion, LF has antioxidant, anti-inflammatory as well as anti-apoptotic effects against CTX-induced POF, and the inhibition of TLR4/NF-κB and apoptosis pathways may be involved in its mechanisms.

Mechanisms of bacterial resistance to environmental silver and antimicrobial strategies for silver: A review.

The good antimicrobial properties of silver make it widely used in food, medicine, and environmental applications. However, the release and accumulation of silver-based antimicrobial agents in the environment is increasing with the extensive use of silver-based antimicrobials, and the prevalence of silver-resistant bacteria is increasing. To prevent the emergence of superbugs, it is necessary to exercise rational and strict control over drug use. The mechanism of bacterial resistance to silver has not been fully elucidated, and this article provides a review of the progress of research on the mechanism of bacterial resistance to silver. The results indicate that bacterial resistance to silver can occur through inducing silver particles aggregation and Ag+ reduction, inhibiting silver contact with and entry into cells, efflux of silver particles and Ag+ in cells, and activation of damage repair mechanisms. We propose that the bacterial mechanism of silver resistance involves a combination of interrelated systems. Finally, we discuss how this information can be used to develop the next generation of silver-based antimicrobials and antimicrobial therapies. And some antimicrobial strategies are proposed such as the "Trojan Horse" - camouflage, using efflux pump inhibitors to reduce silver efflux, working with "minesweeper", immobilization of silver particles.